Current advancements and future perspectives of 1,2,3-triazoles to target lanosterol 14α-demethylase (CYP51), a cytochrome P450 enzyme: A computational approach.

Antifungal resistance has become a significant challenge, necessitating the development of novel antifungal agents. Resistance often arises from prolonged and widespread use of existing treatments, leading to mutations in fungal enzymes that reduce drug efficacy. Amongst various scaffolds, 1,2,3-triazoles have emerged as antifungal agents due to their ability to bind effectively to fungal enzymes. This review examines the binding interactions of 1,2,3-triazoles with lanosterol 14α-demethylase (CYP51), an enzyme in Candida albicans (PDB IDs:5TZ1and5V5Z), highlighting their potential in fighting resistance. The CYP51 family is a captivating topic to investigate the structural and functional roles of P450 and makes for a key medical focus. It is one of crucial step in biosynthesis of sterol in eukaryotes. Antifungals mostly work on CYP51 and could also be used to treat protozoan diseases in the future. 1,2,3-Triazoles exert their antifungal effects by inhibiting the CYP51 enzyme, which is crucial for ergosterol synthesis in fungal cell membranes thereby leading to disruption of membrane integrity and ultimately leads to death of fungal cell. In silico studies like molecular docking and molecular dynamics (MD) simulations, reveal that these compounds establish strong interactions (e.g., π-π, π-alkyl, CH, hydrogen bonding, and Van der Waals interactions) with active site residues, stabilizing the ligand-enzyme complex. This review of virtual screening assays shows the adaptability of the 1,2,3-triazole scaffold and its widespread use in core antifungal compounds, making it a key pharmacophore for new lead development against resistant fungal species.